Adamantylcarboxamidophenylalkanoic acids and esters thereof for treating inflammatory disorders and allergies

ABSTRACT

Pharmaceutical compositions comprising an effective amount of adamantylcarboxamidophenylalkanoic acids, their esters or salts, and a pharmaceutical excipient, are anti-allergic and antiinflammatory agents.

United States Patent [191 Wasley Nov. 18, 1975 ADAMANTYLCARBOXAMIDO-PHENYLALKANOIC ACIDS AND ESTERS THEREOF FOR TREATING INFLAMMATORYDISORDERS AND ALLERGIES A [75] Inventor: Jan W. F. Wasley, Mount Kisco,

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

22 Filed: Apr. 12, 1974 21 Appl. No.: 460,406

Related US. Application Data [52] US. Cl 424/319; 424/309 [51] Int. Cl.A61k 31/195; A61k 31/24 [58] Field of Search 424/317, 319, 308, 309

[56] References Cited UNITED STATES PATENTS 3,766,262 10/1973 Szinai eta1 260/518 R Primary ExaminerStanley J. Friedman Attorney, Agent, orFirmJoseph G. Kolodny; Theodore O. Groeger; John J. Maitner ABSTRACTPharmaceutical compositions comprising an effective amount ofadamantylcarboxamidophenylalkanoic acids, their esters or salts, and apharmaceutical excipient, are anti-allergic and anti-inflammatoryagents.

10 Claims, No Drawings ADAMANTYLCARBOXAMIDOPHENYLALK- ANOIC ACIDS ANDESTERS THEREOF FOR TREATING INFLAMMATORY. DISORDERS AND ALLERGIESCROSS-REFERECES TO RELATED APPLICATIONS This is a continuation-in-partof Ser. No. 311,054, filed Dec. 1, 1972, (now U.S. Pat. No. 3,839,433)which in turn is a continuation-in-part of application Ser. No. 157,770,filed June 28, 1971, which in turn is a continuation-in-part ofapplication Ser. No. 22,406, filed Mar. 24, 1970, which in turn is acontinuation-inpart of application Ser. No. 810,828, filed Mar. 26, 1969(the latter three are abandoned).

SUMMARY OF THE INVENTION The present invention pertains topharmaceutical compositions comprising an effective amount of compoundsof Formula I R and R are hydrogen or lower alkyl; R and R are hydrogen,fluoro, chloro, bromo, lower alkyl, lower alkoxy, or trifluoromethyl;and

n is 0 or 1 or pharmaceutically acceptable non-toxic salts of thosecompounds wherein R is hydrogen, and a pharmaceutical excipient; as wellas to novel methods utilizing said compositions for the treatment ofallergic and inflammatory conditions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The term lower alkyl as usedherein alone or in combination, such as in lower alkoxy, means astraight or branched hydrocarbon chain of the formula C l-I wherein mrepresents an integer of from 1 to 4. Illustrative of such alkyl groupsare methyl, ethyl, propyl, isopropyl, n-, isoor t-butyl; m=l or 2 ispreferred. Illustrative of lower alkoxy groups is methoxy, ethoxy, noriso-propoxy or -butoxy, and the like, preferably methoxy. The preferredalkyl groups for substituent R are methyl and ethyl.

The term pharmaceutically acceptable non-toxic salts means salts formedwith inorganic or organic bases which themselves have no undersirablephysiological action in the usual dosages. Suitable salts are sodium,potassium, magnesium, calcium and ammonium 2 salts and also salts withethylamine, triethylamine, ethanolamine, diethanolamine,ethylenediamine, pyrrolidine, etc.

The unsubstituted and substituted adamantylcarboxamidophenylalkanoicacids and lower alkyl esters can be prepared by reacting aminophenylalkanoic acids and lower alkyl esters with adamantoyl chloride orbromide in an anhydrous solvent, for instance, a mixture of benzene andan organic base, like pyridine. The preferred solvent is pyridine. Theacids or esters can be prepared from one another by subsequenthydrolysis of the esters, for instance, by means of sodium hydroxide orpotassium hydroxide or by esterification of the acids, for instance, bymeans of an esterifying agent, for example, diazomethane or an alcoholwith an acid catalyst. These reactions can be represented'as follows:

wherein R R R, R and n have the meaning as defined in formula I and X ischlorine or bromine.

The aminophenylalkanoic acids and lower alkyl esters are prepared by thereductiion of the corresponding nitro compounds, which may be preparedfrom known chemicals by known procedures.

The compounds of the present invention demonstrate the properties ofinhibiting and reducing inflammation, and of suppressing immuneresponses in warmblooded animals when administered orally orparenterally, and are thus useful as anti-inflammatory agents. Althoughthe mechanism of action of these anti-inflammatory agents is notcompletely understood it may at least in part be traceable to thecompounds ability to suppress antibody formation. Thus while thecompounds can be shown to demonstrate activity inclassical laboratorymodels for testing anti-inflammatory properties such as theanti-carrageenin test, serum turbidity test, adjuvant arthritis test,and antipyretic test, they also demonstrate immune-suppressive activityin the Jerne Hemolytic Plaque Technique.

In addition to the above properties, the compounds of the presentinvention advantageously exhibit antiallergic effects. These can bedemonstrated in animal tests, using advantageously mammals, such asrats, guinea pigs, dogs or monkeys. Compounds of the in- 3 vention canbe administered to the animals either enterally, preferably orally, orparenterally, e.g. subcutaneously, intravenously, for example, in theform of aqueous solutions, suspensions or by means of an aerosol. Theapplied dosage ranges between about 1 and 300 mg/kg/day, preferablybetween about 20 and ZOO/mg/kg/day, or more preferably between 40 and100 mg/kg/day. The tests chosen are the guinea pig anaphylaxis, canineasthma and primate skin allergy. In

each system, various standards are tested for reference purposes.

Thus, for example, the 2-( l-adamantylcarboxamido)phenylacetic acid, arepresentative member of the compounds of formula 1, in the canineasthma model after the induction of an asthmatic attack (therapeutic)showed 70 percent inhibition at 100 mg/kg/po. When administered i.v. at40 mg/kg, said compound gave 40 percent inhibition. The former effect isequivalent to that observed by theophylline. Finally, when mixed withthe inducing antigen (inhalant) at 3 mg/kg, the compound inhibited thereaction 66 percent. In the monkey skin allergy model, the abovecompound gives a dose-related inhibition of the reaction, whereasantihistamines are inactive. In the guinea pig anaphylaxis model,pretreatment with the above compound inhibits the reactions 69 percentat 100 mg/kg/po. It is also noted that said compound, given afteranaphylaxis has occurred, inhibits, 1 hour later (at the time of peakblood levels), the residual bronchoconstriction which clinically resultsin delayed deaths [Collier, H.O.J., et al., Brit. J. Pharmacol.Chemotherap. 30, 283 (1967)]. Anti-histamines do not inhibit thisresidual broncho-constriction indicating that the above compound iscapable of inhibiting mediators of this reaction which are insensitiveto antihistamines. Accordingly, compounds of the invention areantiallergic agents and are useful, for example, in the treatment ormanagement of asthma.

The preferred compounds are those defined in formula I wherein R, R andR are hydrogen, R is hydrogen, fluoro, chloro, bromo, lower alkyl, loweralkoxy, or trifluoromethyl, n is 0, and the alkanoic acid is in theortho-position of the phenyl ring relative to the adamantylcarboxamidogroup. The following compounds are illustrative:

2-( l-adamantylcarboxamido)-4-methylphenylacetic acid,

2-( l -adamantylcarboxamido)-4-trifluoromethylphenylacetic acid,

2-( l-adamantylcarboxamido)-5-fluorophenylacetic acid,

2-( l-adamantylcarboxamido)-5-methoxyphenylacetic acid,

and, above all, the

2-( l -adamantylcarboxamido)phenylacetic acid.

In actual use, the compounds of formula I are administered to mammalsfor the purpose of treating various inflammatory conditions which arecommonly treated with known anti-inflammatory agents, particularly thosein which an immunological mechanism is believed to be present, such asvarious forms of rheumatoid arthritis. The compounds are alsoadministered to mammals for the purpose of treating various allergicconditions, particularly of the asthmatic type. The new compounds areincorporated in compositions suitable for oral administration to mammalsin solid and liquid unit dosage forms, such as tablets, capsules,powders, granules, syrups, elixirs, and the like. The term unit dosageform as used in this specification and claims refers to physicallydiscrete units suitable as unitary dosage for mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical diluent carrier or vehicle. The compositions thus containabout 0.1- percent, preferably about 1-50 percent, of the activeingredient.

Powders are prepared by comminuting a compound of this invention to asuitably fine size and mixing a similarly comminuted diluent. Thediluent can be an edible carbohydrate material such as starch. Asweetening agent or sugar may also be present as well as flavoring oil.

Granules for reconstitution into a liquid oral preparation are preparedutilizing water-soluble diluents. A powder mixture of the finely dividedcompound and water-soluble diluent such as sucrose, glucose, and thelike is wetted with a binder such as acacia mucilage, gelatin solution,methylcellulose solution and forced through a screen to form granuleswhich are allowed to dry. A suspending agent such as tragacanth may beincluded in the composition.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. As an adjuvant to the filling operation,a lubricant such as talc, magnesium stearate and calcium stearate may beadded to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the compound, suitable comminuted, with a diluent orbase such as starch, sucrose, kaolin, dicalcium phosphate and the like.The powder mixture can be granulated by wetting with a binder such asyrup, starch paste or acacia mucilage and forcing through a screen. Asan alternative togranulating, the powder mixture can be slugged, i.e.run through the tablet machine and the resulting imperfectly formedtablets broken into slugs. The slugs can be lubricated to preventsticking to the tablet forming dies by means of the addition of stearicacid, a stearate salt, talc or mineral oil. The lubricating mixture isthem compressed into tablets. A protective coating consisting of asealing coat of shellac, a coating of sugar and methylcellulose, and apolish coating of carnauba wax may be provided.

Oral fluids are prepared in unit dosage forms such as syrups and elixirswherein each teaspoonful of composition contains a predetermined amountof the compound for administration.

A syrup is prepared by suspending the compound in a suitably flavoredaqueous sucrose solution. Similarly,

an elixir is prepared utilizing a non-toxic alcohol vehi-.

cle.

For parenteral administration, aqueous and oleaginous fluid unit dosageforms can be prepared. ln preparing the parenteral form, a measuredamount of the compound is placed in a vial, the vial and its contentssterilized and sealed. An accompanying vial of sterile water may beprovided as a vehicle to form a suspension prior to administration.Particularly suitable for parenteral administration are the additionsalts of the compounds of formula I.

The amount of these compounds which is administered mustin all cases beadjusted to the mammal being treated, its age, weight and condition, aswell as the degree of response required. The actual dose should becarefully titrated to the particular subject in accordance withwell-recognized principles of pharmacology.

The following examples are given by way of illustrating the process forthe preparation of the compounds and the compositions without limitingthe scope thereof an any way. The temperatures are given in degreesCentigrade.

EXAMPLE 1.

Methyl 2-( l-adamantylcarboxamido)phenylacetate v EXAMPLE 2 2-(l-Adamantylcarboxamido)phenylacetic acid A mixture of 23.3 g of methyl2-(1-adamantylcarboxamido)phenylacetate and 100 ml of N sodium hydroxideis heatedunder reflux until a homogeneous solution is obtained; Thesolution is filtered,cooled to room temperature and the pH adjusted to 3with 6N hydrochloric acid. A sticky white solid precipitates which isdissolved in hot ethanol. Sufficient water is then added to inducecrystallization. The desired product is recrystallized from aqueousethanol as colorless needles melting at 23023lC.

EXAMPLE 3 2-( l-Adamantylcarboxamido )-4-methylphenylacetic acid a.Twenty-three grams of sodium metal spheres are added with stirring at amoderate rate to 1 liter of absolute ethanol contained in a 5 literthree-necked flask equipped with stirrer, condenser and dropping funnel.Diethyl malonate (160.2 g) is then added dropwise by means of thedropping funnel, followed by the addition of 171.6 g of3-nitro-4-chloroto1uene. The mixture is heated at reflux for 2.5 hoursafter which the ethanol is distilled off at atmospheric pressure. To thereaction flask is then added 1 liter of absolute ethanol and 1 liter ofpotassium hydroxide and the mixture is then heated at reflux'for 1.5hours, followed by distillation of the ethanol at atmospheric pressure.The solution is cooled to room temperature and extracted twice with 500ml of ether. The basic aqueous layer is adjusted to a pH of l by meansof 6N hydrochloric acid to yield a brown solid. The product iscollectedby filtration and dried for 18 hours at 70C/10 mm. The 4-methyl-2-nitrophenylacetic acid melts at l678C.

b. A mixture of 17.5 g of 4-methyl-2-nitrophenylacetic acid, 250 ml ofabsolute methanol and 5 ml of concentrated sulfuric acid is heated atreflux for 2 hours, then excess solvent is removed by distillation.

The reaction is cooled to room temperature, rendered basic with a 10%ammonium hydroxide solution, diluted with 500 ml of water and twiceextracted with 300 ml of ether. The ether extracts are dried overmagnesium sulfate, clarified, filtered, and evaporated to dryness underreduced pressure to yield methyl 4- methyl-2-nitrophenylacetate as anamber-colored oil.

c. The oil obtained according to part b) of this Example is dissolved in150 m1 of ethyl acetate and l g of 5% palladium on carbon as added ascatalyst. The reaction mixture is hydrogenated at atmospheric pressureuntil three molar equivalents of hydrogen are consumed. The catalyst isremoved by filtration and the filtrate is evaporated to dryness underreduced pressure at 3035C, yielding methyl 2-amino-4-methylphenylacetateas an oil.

d. To a stirred solution of 7.5 g of methyl 2-amino-4-methylphenylacetate in 150 ml of dry pyridine is added 8.4 g ofl-adamantanecarbonyl chloride in one portion, maintaining a reactiontemperature of from 25 to 30C. The mixture is stirred for 15 minutesduring which time pyridinium chloride separates out. The mixture isdiluted with 200 ml of water and the precipitate is collected byfiltration to yield methyl 2-(l-adamantylcarboxamido)-4-methylphenylacetate, m.p. 1445C.

e. A mixture of 12.1 g of a compound according to part d) of thisExample and 150 ml of 0.5N sodium hydroxide solution is heated underreflux until a homogeneous solution is obtained. The solution is cooledto 20C, filtered and adjusted to a pH of 4 with 3N hydrochloric acid.The solid is collected by filtration and is recrystallized from aqueousethanol as colorless plates, m.p. 2l4-2l5C.

EXAMPLE 4 2-( 1-Adamantylcarboxamido)-4-trifluoromethylphenylacetic acida. To a mixture of 17.7 g of methyl2-amino-4-trifluoromethylphenylacetate in 200 ml of dry pyridine areadded 15.1 g of l-adamantanecarbonyl chloride in one portion. Themixture is kept at 20C and is agitated for 5 minutes at which timepyridinium chloride separates. The reaction mixture is diluted with 400ml of water. With further agitation, the product precipitates. The solidis collected by filtration, washed twice with 50 ml of water and driedin vacuo. The obtained methyl 2-(1-adamantylcarboxamido)-4-trifluoromethylphenylacetate melts atl20-122C.

b. A mixture of 30 g of methyl2-(l-adamantylcarboxamido)-4-trifluoromethylphenylacetate and 200 ml of0.5N sodium hydroxide solution is heated under reflux until ahomogeneous solution is obtained. The solution'is clarified, filteredand cooled to room temperature. The pH of the filtrate is adjusted to pH4 with 3N hydrochloric acid, and the solid is collected by filtration.The product is recrystallized from aqueous ethanol as colorless plates,m.p. 218-219C.

EXAMPLE 5 2-( l-Adamantylcarboxamido)-5 -fluorophenylacetic acid a. Amixture of 10 g of 5-fluoro-2-nitrophenylacetonitrile and ml ofconcentrated hydrochloric acid is heated at reflux for minutes. Thereaction mixture is poured into 300 ml of cold water with stirringwhereupon the 5-fluoro-2-nitrophenylacetic acid precipitates. The solidis collected by filtration and is dried in vacuo, m.p. 15l5C.

b. A mixture of 8.1 g of -fluoro-2-nitrophenylacetic acid, 150 ml ofabsolute methanol and 5 ml of concentrated sulfuric acid is heated atreflux for 2 hours. Excess methanol is evaporated, the residue isdiluted with 200 ml of water, and the solution is rendered basic with aammonium hydroxide solution. The basic aqueous layer is extracted twicewith 200 ml of ether. The ethereal extracts are clarified, dried overmagnesium sulfate, and the solvent evaporated under reduced pressure toyield methyl 5-fluoro-2-nitrophenylacetate as an oil.

c. To 7.7 g of methyl 5-fluoro-2-nitrophenylacetate, dissolved in 200 mlof absolute ethanol, are added 1 g of 5% palladium on barium sulfate.The mixture is hydrogenated at atmospheric pressure and at C until threemolar equivalents of hydrogen are consumed. The catalyst is removed byfiltration and the filtrate is evaporated to dryness under reducedpressure to yield methyl 5-fluoro-2-aminophenylacetate as an oil.

(1. A mixture is prepared by dissolving 6.4 g of methyl5-fluoro-2-aminophenylacetate in 150 ml of dry pyridine. 7.2 g ofl-adamantanecarbonyl chloride are added to the stirring pyridinesolution in one portion. The mixture is stirred vigorously for 3 to 5minutes and is then diluted with 400 ml of water precipitating a solidwhich is methyl 2-( l-adamantylcarboxamido)-5- fluorophenylacetate. Theproduct is collected by filtration, washed with water and dried, m.p.l40-l42C.

e. A mixture of l 1.1 g of methyl2(1-adamantylcarboxamido)-5-fluorophenylacetate and 200 ml of 0.5Nsodium hydroxide is heated at refluxing temperature until a homogeneoussolution is obtained. The solution is clarified, filtered, diluted with250 ml of water, cooled to room temperature and rendered acid to a pH of4 with 6N hydrochloric acid. The product is collected by filtration andis recrystallized from aqueous ethanol as colorless needles, m.p.247248C.

EXAMPLE 6 2-( 1-Adamantylcarboxamido)-5-methoxyphenylacetic acid a.5-methoxy-2-nitrophenylacetic acid is prepared according to theprocedure described by C. F. Koelsch, J. Am. Chem. Soc. 66, 2019-20(1944).

b. After dissolving 33 g of 5-methoxy-2-nitrophenylacetic acid in 200 mlof absolute methanol, 5 ml of concentrated sulfuric acid are added. Themixture is heated at reflux for 2 hours. Excess solvent is removed bydistillation, the residue is diluted with 550 ml of water, and thesolution is rendered basic with 10% ammonium hydroxide. The aqueoussolution is extracted with ether (3 X 300 ml). The ethereal extracts areclarified, dried over magnesium sulfate, and the solvent evaporatedunder reduced pressure to yield a solid which is methyl5-methoxy-2-nitrophenylacetate, m.p. l62164C.

c. 34.1 g of Methyl 5-methoxy-2-nitrophenylacetate is dissolved in 200ml of ethyl acetate and 3 g of 5% palladium on barium sulfate is addedas catalyst. The mixture is hydrogenated at atmospheric pressure at 20C,until three molar equivalents of hydrogen have been Consumed. Thecatalyst is separated by filtration and the filtrate is evaporated todryness under reduced pressure to yield methyl5-methoxy-Z-aminophenylacetate as an oil.

d. To a mixture of 9.7 g of methyl 5-methoxy-2- aminophenylacetate in mlof dry pyridine are added 9.9 g of l-adamantanecarbonyl chloride whilestirring. After a few minutes, pyridinium chloride precipitates. Themixture is allowed to stir at room temperature for 10 minutes; then themixture is diluted with 300 ml of water whereupon methyl2-(1-adamantylcarboxamido)-5-methoxy-phenylacetate precipitates. Thesolid is collected by filtration and is washed twice with ml of water.The crude product melts at l63165C.

e. A mixture of 22 g of methylZ-(I-adamantylcarboxamido)-5-methoxyphenylacetate and ml of 0.5N sodiumhydroxide is heated at reflux until a homogeneous solution is obtained.The solution is clarified, filtered, diluted with 200 ml of water,cooled to room temperature and rendered acid with 3N hydrochloric acidto a pH of 4. The solid is collected by filtration, washed with waterand recrystallized from aqueous ethanol, m.p. 188189C.

EXAMPLE 7 2-( l-Adamantylcarboxamido )-4,5-dimethoxyphenylacetic acid a.The starting material methyl 2-amino-4,5-dimethoxyphenylacetate isprepared according to the procedure described by G. N. Walker, J. Am.Chem. Soc. 77, 3844-50 (1955).

b. To a stirring mixture of 21.8 g of methyl 2-amino-4,5-dimethoxyphenylacetate in 150 ml of dry pyridine are added 19.2 g ofl-adamantanecarbonyl chloride while maintaining the reaction temperatureat 30C by means of an ice-water bath. The reaction mixture is agitatedfor 10 minutes at room temperature at which time it is diluted with 400ml of water upon which a viscous oil separates. The aqueous layer isdecanted and the residual oil is solidified upon trituration with 150 mlof ether and scratching. The product is collected by filtration and isrecrystallized from aqueous ethanol to yield methyl2-(1-adamantylcarboxamido)-4,5-dimethoxyphenylacetate melting atl49150C.

c. A mixture of 16.5 g of methyl2-(1-adamantylcarboxamido)-4,5-dimethoxyphenylacetate and 200 ml of 0.5N sodium hydroxide solution is heated at reflux until a homogeneoussolution is obtained. The hot solution is clarified, filtered and cooledto room temperature. The solution is then adjusted to pH 4 with 3Nhydrochloric acid whereupon a solid precipitates. The solid is collectedby filtration and is recrystallized from aqueous ethanol, m.p. 230232C.

EXAMPLE 8 2-[2-( 1-Adamantylcarboxamido)phenyl]propionic acid I a. To asolution of 10.2 g of methyl a-methyl-onitrophenylacetate in 150 ml ofethyl acetate, there is added 1.5 g of 5% palladium on barium sulfate ascata-- lyst. The mixture is hydrogenated at atmospheric pressure androom temperature until three molar equivalents of hydrogen are consumed.The catalyst is removed by filtration and the solvent is evaporated todryness under reduced pressure at 30C. Methylamethyl-o-aminophenylacetate in form of an amber oil is obtained.

b. A solution of 8.3 g of methyl a-methyl-oaminophenylacetate in 150 mlof pyridine is cooled and stirred while 9.14 g of l-adamantanecarbonylchloride are added. After hours a small quantity of water is added, themixture is left to stir at room temperature for 18 hours, is dilutedwith 200 ml of water and is rendered basic with a 5% sodium bicarbonatesolution. The reaction product is extracted'with ether. The etherealextracts are dried and the solvent evaporated to dryness to yield methyl2-[2-( l-adamantylcarboxamido)phenyl]propionate, m.p. 97-99C.

c. The methyl 2-[2-( l-adamantylcarboxamido)- phenyllpropionate obtainedaccording to part b) of this Example is mixed with 0.1 N sodiumhydroxide and the mixture heated at reflux until a homogeneous solutionis obtained. The solution is clarified, filtered, cooled, and the pHadjusted to l. The desired product precipitates. The solid is collectedby filtration and is recrystallized from aqueous ethanol, m.p. l90192C.

EXAMPLE 9 Methyl 2- 2-( 1-adamantylcarboxamido)-4-trifluoromethylphenylpropionate a. To an ice-bath cooled solution of 40.0 g of methyl2-nitro-4-trifluoromethylphenylacetate in 250 ml of dimethylformamide,there is added 6.4 g of 57 percent oil dispersion of sodium hydridefollowed by the addition of 107.9 g of methyl iodide. The mixture isheated at 40C until the color of the solution changed to a deep yellow.The solution is poured into ice-water, extracted .into ether and theethereal solution is washed with water, dried, clarified and filtered.The solvent is evaporated to dryness under reduced pressure. Methyl2-(2- nitro-4-trifluoromethy1phenyl)propionate in form of a yellow oilis obtained.

b. To a solution of 42.5 g of methyl2-(2-nitro-4-trifluoromethylphenyl)propionate in 300 ml of ethylacetate, there is added 5.2 g of 5% palladium on barium sulfate ascatalyst. The mixture is hydrogenated at at-' mospheric pressure androom temperature until three molar equivalents of hydrogen are consumed.The catalyst is removed by filtration and the solvent is evaporated todryness under reduced pressure at 30C. Methyl2-(2-amino-4-trifluoromethylphenyl)propionate in form of a pale yellowoil is obtained.

0. To a stirred solution of 16.6 g of methyl 2-(2-amino-4-trifluoromethylphenyl)propionate in 100 ml of dry pyridine isadded 13.9 g of l-adamantanecarbonyl chloride in one portion,maintaining a reaction temperature of 30-40C. The mixture is stirred for1 hour during which time pyridinium chloride separates out. The mixtureisdiluted with 400 ml of water and the precipitate is collected byfiltration. The solid is recrystallized from aqueous ethanol to yieldmethyl 2-[2-(1- adamantylcarboxamido)-4-trifluoromethylphenyl]propionateas colorless plates, mp. 121-122C.

EXAMPLE 2-[2-( l-Adamantylcarboxamido)-4-trifluoromethylphenyl1propionicacid A mixture of 19.2 g of methyl2-[2-(l-adamantylcarboxamido)-4-trifluroromethylphenyl]propionate and400 ml of 0.45N sodium hydroxide solution is heated under reflux until ahomogeneous solution is obtained. The solution is cooled and extractedtwice with 250 ml of ether. The aqueous layer is then rendered acid topH 1 with 6N hydrochloric acid and the precipitate collected byfiltration. The solid is recrystallized from aqueous ethanol to yield2-[2-(1-adamantylcarboxamido)-4-trif1uoromethylphenyl]propionic acidmelting at 2152l6C.

EXAMPLE 1 1 a. To an ice-bath cooled solution of 27.5 g of methyl2-nitro-4-trifluoromethylphenylacetate in 200 ml of dimethylformamide,there is added 4.4 g of 57% oil dispersion of sodium hydride followed bythe addition of 28.5 g of n-bromobutane. The mixture is heated at 120Cuntil the color of the solution changed to a deep yellow. The solutionis poured into ice-water, extracted into ether and the ethereal solutionis washed with water, clarified, dried and filtered. The solvent isevaporated to dryness under reduced pressure at 30C. Methyl2-(2-nitro-4-trifluoromethylphenyl)hexanoate in form of an amber oil isobtained. The amber oil is distilled under reduced pressure (0.005 mm)and at 100l03C to yield 19.5 g of a yellow oil.

b. To a solution of 19.5 g of methyl2-(2-nitro-4-trifluoromethylphenyl)hexanoate in 250 ml of ethylacetate,there is added 3.5 g of 5% palladium on barium sulfate as'catalyst. Themixture is hydrogenated at atmospheric pressure and room temperatureuntil three molar equivalents of hydrogen are consumed. The catalyst isremoved by filtration and the solvent is evaporated to dryness underreduced pressure at 30C. Methyl2-(2-amino-4-trifluoromethylphenyl)hexanoate in form of a pale yellowoil is obtained.

0. To a stirred solution of 17.6 g of methyl 2-(2-amino-4-trifluoromethylphenyl)hexanoate in 50 ml of dry pyridine isadded 12.3 g of l-adamantanecarbonyl chloride in one portion,maintaining a reaction temperature of from 3045C. The mixture is stirredfor 1 hour during which time pyridium chloride separates out. Themixture is diluted with 400 ml of water and the precipitate is collectedby filtration. The solid is recrystallized from aqueous ethanol to yieldmethyl 2-[2-(1- adamantylcarboxamido )-4-trifluoromethylphenyllhexanoateas colorless crystals, m.p. l72l28C.

EXAMPLE l2 2-[2-(l-Adamantylcarboxamido)-4-trifluoromethylphenyl]hexanoic acid A mixtureof 18.7 g of methyl 2-[2-(l-adamantylcarboxamido)-4-trifluoromethylphenyl]hexanoate, 32.8 g ofsodium bicarbonate, 300 ml of methanol and 20 ml of water is heated at80C for 18 hours. The solution is evaporated to dryness under reducedpressure and is diluted with 400 ml of water. The solution is extractedtwice with 250 m1 of ether and the aqueous layer is rendered acid to pH1 with 6N hydrochloric acid. The aqueous layer is extracted with etherand the ethereal solution is washed with water, charcoaled, dried andfiltered. The solvent is evaporated to dryness and the solid obtainedrecrystallized from ether-petroleum ether (b.p. 30-40C) to yield2-[2-(l-adamantylcarboxamido)-4-trifluoromethylphenyl]hexanoic acidmelting at l171.5C.

EXAMPLE 13 Sodium 2-( l-adamantylcarboxamido)phenylacetate 7.8 g of thecompound of Example 2 was dissolved in ca. 200 ml of methanol and 1.34 gof sodium methoxide was added to the solution. The solvent was thenremoved by evaporation under reduced pressure to yield a white foam. Theproduct was crystallized twice by suspending the solid in hot acetone(100 ml) and adding methanol (ca. 20 ml) to effect solution. The productcrystallized overnight at room temperature, m.p. 237-240C.

I EXAMPLE l4 2-( l-Adamantylcarboxamido )phenylacetic acid A2-aminophenylacetic acid (3.02 g) is dissolved in dry pyridine (50 mland cooled to and l-adamantane carbonyl chloride (3.97 g) isadded slowlywith vigorous stirring. On completion of the addition, the reaction isstirred at room temperature for 1 hour, the pyridine hydrochlorideformed during the reaction is then separated by filtration. After theaddition of water (250 ml) to the filtrate the desired product isextracted into chloroform (250 ml). The chloroform extract is washedwith water (750 ml; 3 X 250 ml) and dried over magnesium sulfate and thesolvent is evaporated under reduced pressure. The product is purified bypartitioning the crude material between the sodium bicarbonate solutionand ether. The aqueous solution is separated and acidified with 6Nhydrochloric acid, whereby the product precipitates as a sticky whitesolid, which is collected by filtration. The desired product isrecrystallized from aqueous ethanol as colorless needles melting at23023lC.

EXAMPLE l 3-( l-Adamantylcarboxamido)phenylacetic acid a. A mixture isprepared from 10 g of methyl 3- aminophenylacetate and 150 ml of drypyridine, and 10.2 g of l-adamantanecarbonyl chloride are added in oneportion to the stirring solution. The reaction is stirred for 10 minutesat which time it is diluted with 300 ml of water precipitating methyl3-( l-adamantylcarboxamido)phenylacetate as a white solid. The productis collected by filtration, washed with water (3 X 100 ml) and dried invacuo, m.p. l32l33C.

b. A mixture of 16.4 g of methyl 3-(l-adamantylcarboxamido)phenylacetate and 200 ml of 0.5N sodium hydroxidesolution is heated at reflux until a homogeneous solution is obtained.The solution is filtered, the filtrate diluted with 400 ml of water andthe pH adjusted to 4 with 6N hydrochloric acid whereupon the desiredproduct precipitates. The product is collected by filtration, washedwith water (3 X 100 ml) and recrystallized from aqueous ethanol, m.p.203-204C.

EXAMPLE [6 4-( l-Adamantylcarboxamido)phenylacetic acid a. To a mixtureof 16.5 g of methyl 4-aminophenylacetate in 100 ml of dry pyridine areadded 19.5 g of l-adamantanecarbonyl chloride while maintaining thereaction temperature between 2530C. On completion of addition,pyridinium chloride separates out and the reaction mixture is stirredfor further minutes at room temperature after which time it is dilutedwith 200 ml of water yielding methyl 4-(l-adamantylcarboxamido)phenylacetate as a copious precipitate. The solidis collected by filtration and dried, m.p. l55l56C.

b. A mixture of 18 g of methyl 4-(l-adamantylcarboxamido)phenylacetateand 200 ml of 0.5N sodium hydroxide is heated at reflux until ahomogeneous solution is obtained. The solution is cooled to 35C and thesodium salt separates out. The solid is collected by filtration and isdried in vacuo. The sodium salt is recrystallized from water, m.p.294295C. The salt is then dissolved in 250 ml of water and the solutionis adjusted to pH 4 by means of 3N hydrochloric acid. The formed acid iscollected by filtration and recrystallized from aqueous ethanol to yieldthe desired product in form of colorless plates, m.p. 193194C.

EXAMPLE l7 3-[2-( l-Adamantylcarboxamido)phenyl]propionic acid a. Asolution of 23.4 g of methyl-o-aminocinnamate in 200 ml of pyridine isstirred while 262 g of ladamantanecarbonyl chloride are added. Thereaction mixture is stirred at room temperature for 15-20 minutes and isthen diluted with 500 ml of water yielding a precipitate. The suspensionis left stirring overnight at room temperature. The solid is collectedby filtration and is recrystallized from aqueous ethanol. Therecrystallized material is collected by filtration and is washed withcold ether to yield methyl 2-( l-adamantylcarboxamido)cinnamate as anoff-white colored solid, m.p. ll72C.

To a solution of 8.5 g of methyl Z-(I-adamantylcarboxamido)cinnamate in200 ml of absolute ethanol and 5 ml of glacial acetic acid, there isadded 1.5 g of 5% palladium on barium as catalyst. The mixture ishydrogenated at atmospheric pressure and room temperature until onemolar equivalent of hydrogen is consumed. The catalyst is'removed byfiltration and the filtrate is evaporated to dryness to yield methyl3-[2-( l-adamantylcarboxamido)phenyllpropionate, m.p. lO6-l08C.

c. A mixture of 7.8 g of methyl 3-[2-(l-adamantylcarboxamido)phenyllpropionate and 300 ml of 0.1N sodiumhydroxide is heated at reflux until a homogeneous solution is obtained.The solution is clarified, filtered, cooled, and rendered acid with 6Nhydrochloric acid to pH 1 yield the desired product in form of a whiteprecipitate. The solid is collected by filtration and is recrystallizedfrom aqueous ethanol as colorless plates, m.p. l92-l93C.

EXAMPLE l8 Ingredient Quantity! capsule 2-( l-Adamantylcarboxamido)-phenylacetic acid Corn starch, U.S.P.

mg 200 mg The foregoing ingredients are mixed and introduced onto atwo-piece No. 1 hard gelatin capsule.

The foregoing ingredients are thoroughly mixed and pressed into tabletssuitable for oral administration of 50 g of active ingredient. Thetablets may be scored to permit administration of fractional doses.

The first three ingredients are thoroughly mixed and granulated with asolution of the soluble starch. This granulate is dried, mixed with themagnesium stearate and pressed into tablet cores which are coated aswith sugar.

The first three ingredients are thoroughly mixed, wetted with theethanol and granulated. The dried granulate is mixed with the magnesiumstearate and com: pressed into round, biconvex tablets, about 4 mm thickand 7 mm in diameter.

EXAMPLE 22 Ingredients Quantity/dosage unit 2 l adamantylcarboxamidoyphenylacetic acid 400 mg Sodium carbonate, anhydrous 140 mg Sodiumsaccharin 120 mg Freeze-dried coffee 200 mg Distilled water 40 ml Thepowders are dry-mixed until uniform. For oral administration each doseis dissolved in 40 ml of water.

I claim:

1. An antiallergic pharmaceutical composition comprising anantiallergically effective amount of a com; pound of the formula ICH-(CH -cooR 2 n wherein R is hydrogen or lower alkyl, R is hydrogen orlower alkyl, R and R are hydrogen, fluorine, chlorine, bromine, loweralkyl, lower alkoxy or trifluoromethyl, and n is 0 or I, or an alkalimetal or ammonium salt thereof, together with a pharmaceuticalexcipient.

2. A composition as claimed in claim 1, in which compound R, R and R arehydrogen, R is hydrogen, fluorine, chlorine, bromine, lower alkyl, loweralkoxy or trifluoromethyl, n is zero and the alkanoic acid group is in 2position of the phenyl ring, or R is an alkali metal or ammonium.

3. A composition as claimed in claim 1, wherein said compound is the 2-(l adamantylcarboxamidoy phenylacetic acid.

4. A composition as claimed in claim 1, wherein said compound is the 2;(l-adamantylcarboxamido)-4- methylphenylacetic acid.

5. A composition as claimed in claim 1, wherein said compound is the 2 ladamantylcarboxamido )-4-trifluoromethylphenylacetic acid.

6. A composition as claimed in claim 1, wherein said compound is the2-(1-adamantylcarboxamido)-5- fluorophenylacetic acis.

7. A composition as claimed in claim 1, wherein said compound is the 2-(l-adamantylcarboxamido)-5- methoxyphenylacetic acid.

8. A composition as claimed in claim 1, wherein an enterally acceptableexcipient is used.

9. A method for treating a mammal suffering from inflammatory disorders,comprising administering to said mammal a therapeutically effectiveamount of a composition as claimed in claim 1.

10. A method for treating a mammal suffering from allergies, comprisingadministering to said mammal a therapeutically effective amount of acomposition as claimed in claim 1.

2. A composition as claimed in claim 1, in which compound R1, R2 and R4are hydrogen, R3 is hydrogen, fluorine, chlorine, bromine, lower alkyl,lower alkoxy or trifluoromethyl, n is zero and the alkanoic acid groupis in 2-position of the phenyl ring, or R1 is an alkali metal orammonium.
 3. A composition as claimed in claim 1, wherein said compoundis the 2-(1-adamantylcarboxamido)-phenylacetic acid.
 4. A composition asclaimed in claim 1, wherein said compound is the2-(1-adamantylcarboxamido)-4-methylphenylacetic acid.
 5. A compositionas claimed in claim 1, wherein said compound is the2-(1-adamantylcarboxamido)-4-trifluoromethylphenylacetic acid.
 6. Acomposition as claimed in claim 1, wherein said compound is the2-(1-adamantylcarboxamido)-5-fluorophenylacetic acis.
 7. A compositionas claimed in claim 1, wherein said compound is the2-(1-adamantylcarboxamido)-5-methoxyphenylacetic acid.
 8. A compositionas claimed in claim 1, wherein an entErally acceptable excipient isused.
 9. A method for treating a mammal suffering from inflammatorydisorders, comprising administering to said mammal a therapeuticallyeffective amount of a composition as claimed in claim
 1. 10. A methodfor treating a mammal suffering from allergies, comprising administeringto said mammal a therapeutically effective amount of a composition asclaimed in claim 1.